EP2861245B1 - Cationic lipid vaccine compositions and methods of use - Google Patents

Cationic lipid vaccine compositions and methods of use Download PDF

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Publication number
EP2861245B1
EP2861245B1 EP13804165.2A EP13804165A EP2861245B1 EP 2861245 B1 EP2861245 B1 EP 2861245B1 EP 13804165 A EP13804165 A EP 13804165A EP 2861245 B1 EP2861245 B1 EP 2861245B1
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Prior art keywords
antigen
group
tumor
vaccine composition
dotap
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English (en)
French (fr)
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EP2861245A4 (en
EP2861245A2 (en
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Mikayel MKRTICHYAN
Samir N. Khleif
Kenya JOHNSON
Eric Jacobson
Frank Bedu-Addo
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US Department of Health and Human Services
PDS Biotechnology Corp
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PDS Biotechnology Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55516—Proteins; Peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55522—Cytokines; Lymphokines; Interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
    • A61K2039/585—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation wherein the target is cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/20011—Papillomaviridae
    • C12N2710/20034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • a vaccine composition includes an antigen to stimulate a targeted immune response.
  • some developmental vaccines are ineffective because they are weak stimulators of an immune response in a broad mammalian population.
  • the antigen in the vaccine composition may be poorly immunogenic in the mammal.
  • some vaccines may not efficiently deliver antigens to the antigen presenting cells ("APCs") of the mammal's immune system.
  • APCs antigen presenting cells
  • MDSCs Myeloid-derived suppressor cells
  • CD4 + and CD8 + T cells Myeloid-derived suppressor cells
  • MDSCs are known to secrete immunosuppressive cytokines and induce regulatory T cell development.
  • MDSCs are induced by pro-inflammatory cytokines and are found in increased numbers in infectious and in inflammatory pathological conditions.
  • MDSCs accumulate in the blood, bone marrow, and secondary lymphoid organs of tumor-bearing mice and their presence in the tumor microenvironment has been suggested to have a causative role in promoting tumor-associated immune suppression.
  • tumor antigen-specific T-cell tolerance has been reported to be a critical element of tumor escape.
  • MDSCs have been found to be present in most cancer patients.
  • Significant research is currently being conducted within the industry to identify a means of inhibiting immune suppressive cells, for example MDSCs and T-regulatory cells, as a means of improving the T-cell responses to attack and kill the infected cells.
  • Current practice in the industry focuses on exploring the use of blocking antibodies to block and inhibit relevant immune suppressive factors.
  • a vaccine such as the human antibody Ipilimumab may be used to block cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), known to play a role in regulating immune responses as a therapeutic vaccine to treat melanoma.
  • CTL-4 cytotoxic T-ly
  • Vaccines also typically include adjuvants in an attempt to enhance the efficacy of antigens in the vaccine composition.
  • adjuvants such as water-in-oil emulsions, alum (e.g., aluminum salts), and other chemicals are typically utilized to enhance antigen response in a mammal.
  • alum e.g., aluminum salts
  • other adjuvants with intrinsic immune effects e.g., influenza virosomes and Chiron's MF59
  • these adjuvants are also undesirable because evidence from animal models (according to clinical trial reports on HSV and influenza vaccines) suggests that they merely enhance production of neutralizing antibodies rather than enhancing T-cell responses in animals.
  • US20110110972 discloses a composition and a method for activating immune cells ex-vivo, or inducing an immune response in a subject including a composition comprising at least one chiral cationic lipid.
  • EP2167480 discloses adjuvants, immunogenic compositions, and methods useful for vaccination and immune response.
  • the disclosure provides a class of adjuvants comprising cationic lipid-lipid mixtures and methods for delivering formulated compositions.
  • US20120148622 discloses the addition of cytokines to enhance the vaccine effectiveness.
  • the present invention relates to a vaccine composition for use as defined in the set of claims.
  • the present disclosure provides vaccine compositions and method of using the compositions that exhibit desirable properties and provide related advantages for improvement in reducing an immune suppressor cell population and augmenting an immune response in a mammal.
  • the present disclosure provides vaccine compositions comprising at least one adjuvant and at least one therapeutic factor.
  • the disclosure also provides methods of reducing an immune suppressor cell population in a mammal, methods of augmenting an immune response in a mammal, and methods of treating a disease in a mammal utilizing the vaccine compositions.
  • the vaccine compositions and methods according to the present disclosure provide several advantages compared to other compositions and methods in the art.
  • the vaccine compositions include an adjuvant that is an immunomodulator to enhance, direct, or promote an appropriate immune response in a mammal.
  • Immunomodulators have the potential to effectively boost a mammal's immune response to antigens if they are included in a vaccine composition.
  • an immunomodulator may advantageously accomplish one or more of the following: (1) improve antigen delivery and/or processing in the APC, (2) induce the production of immunomodulatory cytokines that favor the development of immune responses to the antigen, thus promoting cell mediated immunity, including cytotoxic T-lymphocytes ("CTL"), (3) reduce the number of immunizations or the amount of antigen required for an effective vaccine, (4) increase the biological or immunological half-life of the vaccine antigen, and (5) overcome immune tolerance to antigen by inhibiting immune suppressive factors.
  • CTL cytotoxic T-lymphocytes
  • cationic lipid-based adjuvants may be utilized potent immunomodifying adjuvants and can elicit superior T-cell and antibody immune responses in vaccine compositions.
  • the vaccine compositions in the current disclosure include a therapeutic factor such as a cytokine that as a combination can reduce an immune suppressor cell population in a mammal, which can improve the immune response of a mammal in response to disease.
  • a therapeutic factor such as a cytokine
  • Current research to identify means to inhibit immune suppressive cells such as MDSC and T-regulatory cells utilize complex blocking antibodies. Consequently, administration of a potent vaccine composition including a therapeutic factor such as a cytokine can be easier to administer to a patient and improve immune response, particularly in tumors.
  • the vaccine compositions in the current disclosure including a therapeutic factor can cause a reduction in MDSC both with and without a disease-specific antigen, thus resulting in a unique and powerful approach to treating diseases such as cancer by facilitating the natural activation of antigen-specific T-cells while simultaneously reducing the immune suppressor cell population.
  • the vaccine compositions including a therapeutic factor result in the generation of superior disease-specific immune responses, which are not observed when either the adjuvant or the therapeutic factor alone is formulated with the antigen.
  • the therapeutic factor when combined with cationic lipid adjuvant to form the vaccine composition, results in a unique synergistic improvement in immune response in a mammal.
  • Combinations of therapeutic factor e.g., GM-CSF
  • other adjuvants e.g., incomplete Freund's adjuvant (IFA) or anti-CD40 + IFA
  • IFA incomplete Freund's adjuvant
  • the combination of the cationic lipid adjuvant and the therapeutic factor specifically and significantly result in a synergistic improvement in immune response that cannot be replicated using other commonly used adjuvants.
  • the present invention relates to a vaccine composition for use as defined in the set of claims.
  • a vaccine composition comprises an adjuvant and a therapeutic factor.
  • a method of reducing an immune suppressor cell population in a mammal comprises the step of administering an effective amount of a vaccine composition to the mammal, wherein the vaccine composition comprises an adjuvant and a therapeutic factor.
  • a method of augmenting an immune response in a mammal comprises the step of administering an effective amount of a vaccine composition to the mammal, wherein the vaccine composition comprises an adjuvant and a therapeutic factor.
  • a method of treating a disease in a mammal comprises the step of administering an effective amount of a vaccine composition to the mammal, wherein the vaccine composition comprises an adjuvant and a therapeutic factor.
  • the vaccine composition comprises an adjuvant and a therapeutic factor.
  • adjuvant refers to a substance that enhances, augments and/or potentiates a mammal's immune response to an antigen.
  • therapeutic factor refers to any agent associated with the treatment of disease by inducing, enhancing, or suppressing an immune response.
  • a therapeutic factor includes but is not limited to an immune system stimulant, a cell killing agent, a tumor penetration enhancer, a chemotherapeutic agent, or a cytotoxic immune cell.
  • the vaccine composition includes formulations in which the adjuvant and the therapeutic factor are administered together, as well as formulations in which the adjuvant and the therapeutic factor are administered separately. Doses of the adjuvant and the therapeutic factor are known to those of ordinary skill in the art.
  • the adjuvant is an immunomodulator.
  • immunomodulator refers to an immunologic modifier that enhances, directs, and/or promotes an immune response in a mammal.
  • the adjuvant is a nanoparticle.
  • nanoparticle refers to a particle having a size measured on the nanometer scale.
  • nanoparticle refers to a particle having a structure with a size of less than about 1,000 nanometers.
  • the nanoparticle is a liposome.
  • the adjuvant is a cationic lipid.
  • cationic lipid refers to any of a number of lipid species which carry a net positive charge at physiological pH or have a protonatable group and are positively charged at pH lower than the pKa.
  • Suitable cationic lipid according to the present disclosure include, but are not limited to: 3-.beta.[.sup.4N-(.sup.lN, .sup.8-diguanidino spermidine)-carbamoyl]cholesterol (BGSC); 3-.beta.
  • the cationic lipid is selected from the group consisting of DOTAP, DOTMA, DOEPC, and combinations thereof. In other embodiments, the cationic lipid is DOTAP. In yet other embodiments, the cationic lipid is DOTMA. In other embodiments, the cationic lipid is DOEPC. In some embodiments, the cationic lipid is purified.
  • the cationic lipid is an enantiomer of a cationic lipid.
  • the term "enantiomer" refers to a stereoisomer of a cationic lipid which is a non-superimposable mirror image of its counterpart stereoisomer, for example R and S enantiomers.
  • the enantiomer is R-DOTAP or S-DOTAP.
  • the enantiomer is R-DOTAP.
  • the enantiomer is S-DOTAP.
  • the enantiomer is purified.
  • the enantiomer is R-DOTMA or S-DOTMA.
  • the enantiomer is R-DOTMA.
  • the enantiomer is S-DOTMA. In some embodiments, the enantiomer is purified. In various examples, the enantiomer is R-DOPEC or S-DOPEC. In one example, the enantiomer is R-DOPEC. In another example, the enantiomer is S-DOPEC. In some embodiments, the enantiomer is purified.
  • the therapeutic factor is selected from the group consisting of interleukins 1-18, stem cell factor, basic FGF, EGF, G-CSF, GM-CSF, FLK-2 ligand, HILDA, MIP-1 ⁇ , TGF- ⁇ , TGF- ⁇ , M-CSF, IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , soluble CD23, LIF, and combinations thereof.
  • Other therapeutic factors are known to those of ordinary skill in the art and may also be used in the vaccine compositions of the present disclosure.
  • the therapeutic factor is a cytokine.
  • the cytokine is GM-CSF.
  • the therapeutic factor is an immune cell growth factor.
  • the composition further comprises one or more antigens.
  • antigen refers to any agent (e.g., protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleic acid, or combination thereof) that, when introduced into a mammal having an immune system (directly or upon expression as in, e.g., DNA vaccines), is recognized by the immune system of the mammal and is capable of eliciting an immune response.
  • the antigen-induced immune response can be humoral or cell-mediated, or both.
  • An agent is termed "antigenic” when it is capable of specifically interacting with an antigen recognition molecule of the immune system, such as an immunoglobulin (antibody) or T cell antigen receptor (TCR).
  • one or more antigens is a protein-based antigen. In other embodiments, one or more antigens is a peptide-based antigen. In various embodiments, one or more antigens is selected from the group consisting of a cancer antigen, a viral antigen, a bacterial antigen, and a pathogenic antigen.
  • a "microbial antigen,” as used herein, is an antigen of a microorganism and includes, but is not limited to, infectious virus, infectious bacteria, infectious parasites and infectious fungi.
  • Microbial antigens may be intact microorganisms, and natural isolates, fragments, or derivatives thereof, synthetic compounds which are identical to or similar to naturally-occurring microbial antigens and, preferably, induce an immune response specific for the corresponding microorganism (from which the naturally-occurring microbial antigen originated).
  • the antigen is a cancer antigen.
  • the antigen is a viral antigen.
  • the antigen is a bacterial antigen.
  • the antigen is a pathogenic antigen.
  • the pathogenic antigen is a synthetic or recombinant antigen.
  • the antigen is a cancer antigen.
  • a “cancer antigen,” as used herein, is a molecule or compound (e.g., a protein, peptide, polypeptide, lipoprotein, lipopeptide, glycoprotein, glycopeptides, lipid, glycolipid, carbohydrate, RNA, and/or DNA) associated with a tumor or cancer cell and which is capable of provoking an immune response (humoral and/or cellular) when expressed on the surface of an antigen presenting cell in the context of an MHC molecule.
  • a cancer antigen may be a tumor-associated antigen.
  • Tumor-associated antigens include self antigens, as well as other antigens that may not be specifically associated with a cancer, but nonetheless enhance an immune response to and/or reduce the growth of a tumor or cancer cell when administered to a mammal.
  • at least one antigen is an HPV protein or peptide.
  • At least one antigen comprises a sequence selected from the group consisting of RAHYNIVTF (SEQ. ID. NO: 1), GQAEPDRAHYNIVTF (SEQ. ID. NO: 2), KSSGQAEPDRAHYNIVTF (SEQ. ID. NO: 3), YMLDLQPETT (SEQ. ID. NO: 4), KSSYMLDLQPETT (SEQ. ID. NO: 5), MHGDTPTLHEYMLDLQPETT (SEQ. ID. NO: 6), LLMGTLGIVCPICSQKP (SEQ. ID. NO: 7), KVPRNQDWL (SEQ. ID. NO: 8), SYVDFFVWL (SEQ. ID.
  • At least one antigen comprises the sequence RAHYNIVTF (SEQ. ID. NO: 1). In another embodiment, at least one antigen comprises the sequence GQAEPDRAHYNIVTF (SEQ. ID. NO: 2). In yet another embodiment, at least one antigen comprises the sequence KSSGQAEPDRAHYNIVTF (SEQ. ID. NO: 3). In some embodiments, KSSGQAEPDRAHYNIVTF (SEQ. ID. NO: 3) is modified to further comprise a hydrophobic group. In one embodiment, the hydrophobic group is a palmitoyl group.
  • At least one antigen comprises the sequence YMLDLQPETT (SEQ. ID. NO: 4). In another embodiment, at least one antigen comprises the sequence KSSYMLDLQPETT (SEQ. ID. NO: 5). In yet another embodiment, KSSYMLDLQPETT (SEQ. ID. NO: 5) is modified to further comprise a hydrophobic group. In one embodiment, the hydrophobic group is a palmitoyl group.
  • At least one antigen comprises the sequence MHGDTPTLHEYMLDLQPETT (SEQ. ID. NO: 6).
  • MHGDTPTLHEYMLDLQPETT (SEQ. ID. NO: 6) is modified to further comprise a hydrophobic group.
  • the hydrophobic group is a palmitoyl group.
  • At least one antigen comprises the sequence LLMGTLGIVCPICSQKP (SEQ. ID. NO: 7).
  • LLMGTLGIVCPICSQKP (SEQ. ID. NO: 7) is modified to further comprise a hydrophobic group.
  • the hydrophobic group is a palmitoyl group.
  • At least one antigen comprises the sequence KVPRNQDWL (SEQ. ID. NO: 8). In other embodiments, at least one antigen comprises the sequence SYVDFFVWL (SEQ. ID. NO: 9). In yet other embodiments, at least one antigen comprises the sequence KYICNSSCM (SEQ. ID. NO: 10). In another embodiment, at least one antigen comprises the sequence KSSKVPRNQDWL (SEQ. ID. NO: 11). In some embodiments, KSSKVPRNQDWL (SEQ. ID. NO: 11) is modified to further comprise a hydrophobic group. In one embodiment, the hydrophobic group is a palmitoyl group.
  • At least one antigen comprises the sequence KSSMHGDTPTLHEYMLDLQPETT (SEQ. ID. NO: 12).
  • KSSMHGDTPTLHEYMLDLQPETT (SEQ. ID. NO: 12) is modified to further comprise a hydrophobic group.
  • the hydrophobic group is a palmitoyl group.
  • At least one antigen comprises the sequence KSSLLMGTLGIVCPICSQKP (SEQ. ID. NO: 13).
  • KSSLLMGTLGIVCPICSQKP (SEQ. ID. NO: 13) is modified to further comprise a hydrophobic group.
  • the hydrophobic group is a palmitoyl group.
  • the antigen comprises the sequence selected from the group comprising of gp100 (KVPRNQDWL [SEQ. ID. No. 8]), TRP2 (SYVDFFVWL [SEQ. ID. No. 9]), and p53 (KYICNSSCM [SEQ. ID. No. 10]), and combinations thereof.
  • the antigens comprise one or more of the gp100 sequence (KVPRNQDWL [SEQ. ID. No. 8]) and the TRP2 sequence (SYVDFFVWL [SEQ. ID. No. 9]).
  • At least one antigen is selected from the group consisting of a lipoprotein, a lipopeptide, and a protein or peptide modified with an amino acid sequence having an increased hydrophobicity or a decreased hydrophobicity.
  • one or more antigens is an antigen modified to increase hydrophobicity of the antigen.
  • at least one antigen is a modified protein or peptide.
  • the modified protein or peptide is bonded to a hydrophobic group.
  • the modified protein or peptide bonded to a hydrophobic group further comprises a linker sequence between the antigen and the hydrophobic group.
  • the hydrophobic group is a palmitoyl group.
  • at least one antigen is an unmodified protein or peptide.
  • the vaccine composition induces an immune response in a mammal by activating the mitogen-activated protein (MAP) kinase signaling pathway.
  • MAP mitogen-activated protein
  • Induction of an immune response by adjuvants such as cationic lipids are described, for example, in PCT/US2008/057678 ( WO/2008/116078 ; "Stimulation of an Immune Response by Cationic Lipids") and PCT/US2009/040500 ( WO/2009/129227 ; "Stimulation of an Immune Response by Enantiomers of Cationic Lipids").
  • the MAP kinase signaling pathway is activated by stimulating at least one of extracellular signal-regulated kinase ("ERK")-1, ERK-2, and p38.
  • the composition enhances functional antigen-specific CD8+ T lymphocyte response.
  • ERK extracellular signal-regulated kinase
  • p38 extracellular signal-regulated kinase
  • the composition enhances functional antigen-specific CD8+ T lymphocyte response.
  • the term "mammal" is well known to those of skill in the art. In one embodiment, the mammal is a human.
  • a method of reducing an immune suppressor cell population in a mammal comprises comprising the step of administering an effective amount of a vaccine composition to the mammal, wherein the vaccine composition comprises an adjuvant and a therapeutic factor.
  • the vaccine composition comprises an adjuvant and a therapeutic factor.
  • the immune suppressor cell is a myeloid-derived suppressor cell (MDSC). In other embodiments, the immune suppressor cell is a T regulatory cell.
  • MDSC myeloid-derived suppressor cell
  • the reduction results in an increase in T-cell response in the mammal.
  • the T-cell is a tumor-infiltrated T-cell.
  • the T-cell response is a CD4+ T-cell response.
  • the CD4+ T-cell is a tumor-infiltrated CD4+ T-cell.
  • the T-cell response is a CD8+ T-cell response.
  • the CD8+ T-cell is a tumor-infiltrated CD8+ T-cell.
  • the mammal is a human.
  • the administration activates an immune response via the MAP kinase signaling pathway in cells of the immune system of the mammal.
  • the MAP kinase signaling pathway is activated by stimulating at least one of ERK-1, ERK-2, and p38.
  • the immune response activates cytotoxic T lymphocytes in the mammal.
  • the cytotoxic T lymphocytes are CD8+ T cells.
  • the administration enhances functional antigen-specific CD8+ T lymphocyte response.
  • the immune response activates an antibody response in the mammal.
  • the immune response activates interferon-gamma (IFN- ⁇ ) in the mammal.
  • IFN- ⁇ interferon-gamma
  • a method of augmenting an immune response in a mammal comprises the step of administering an effective amount of a vaccine composition to the mammal, wherein the vaccine composition comprises an adjuvant and a therapeutic factor.
  • the vaccine composition and of the method of reducing an immune suppressor cell population in a mammal are applicable to the method of augmenting an immune response in a mammal described herein.
  • a method of treating a disease in a mammal comprises the step of administering an effective amount of a vaccine composition to the mammal, wherein the vaccine composition comprises an adjuvant and a therapeutic factor.
  • the vaccine composition and of the method of reducing an immune suppressor cell population in a mammal are applicable to the method of treating a disease in a mammal described herein.
  • treatment refers to a prophylactic treatment which increases the resistance of a subject to infection with a pathogen or decreases the likelihood that the subject will become infected with the pathogen; and/or treatment after the subject has become infected in order to fight the infection, e.g., reduce or eliminate the infection or prevent it from becoming worse.
  • the method is a prophylactic treatment.
  • the disease is a cancer.
  • Adjuvants may be prepared using cationic lipids alone. Alternatively, adjuvants may be prepared using mixtures of cationic lipids and other immunomodulators. Vaccine compositions may be prepared using a cationic lipid-based composition incorporating an antigen. In the present example, DOTAP was used as an exemplary cationic lipid and HPV protein E7 peptide antigen was used as an exemplary antigen.
  • Sterile water for injection (WFI) or a buffer was used in all procedures in which cationic lipids were prepared into liposomes.
  • liposomes were prepared using lipid films.
  • the E7 antigen used for incorporation into the liposomes was an H-2D b restricted CTL epitope (amino acid 49-57, RAHYNIVTF [SEQ. ID. NO. 1]) derived from HPV 16 E7 protein.
  • Lipid films were made in glass vials by (1) dissolving the lipids in an organic solvent such as chloroform, and (2) evaporating the chloroform solution under a steady stream of dry nitrogen gas. Traces of organic solvent were removed by keeping the films under vacuum overnight. The lipid films were then hydrated by adding the required amount of WFI or buffer to make a final concentration of 4-10 mg/mL. The suspensions were then extruded to a size of 200 nm and stored at 4°C.
  • the DOTAP lipid film was rehydrated by an aqueous solution of E7 peptide.
  • Other methods used in general liposome preparation that are well known to those skilled in the art may also be used.
  • compositions may be compared according to the present disclosure and evaluated for their effects on antigen-specific immune response in tumor-bearing mice.
  • R-DOTAP was used as an exemplary cationic lipid
  • E7 peptide was used as an exemplary antigen
  • the cytokine GM-CSF was used as an exemplary therapeutic factor.
  • anti-CD40 Ab and incomplete Freund's adjuvant (IFA) were used as comparative adjuvants.
  • vaccine compositions were prepared according to the disclosure and the following groups were evaluated:
  • mice Female C57BL6 mice aged 6-8 weeks old (5 mice per group) were implanted with 50,000 TC-1 cells/mouse subcutaneously in the right flank on day 0. On day 8, when all mice had tumors of ⁇ 3-4 mm in diameter, subjects from each group were with the vaccine composition of the appropriate group.
  • mice were sacrificed.
  • the spleens of the mice were harvested and processed for total lymphocytes.
  • IFN ⁇ activity in the presence of E7 49-57 peptide vs. irrelevant peptide control (10 ⁇ g/ml each) was assayed by ELISPOT.
  • the number of spots from E7 49-57 re-stimulated culture minus irrelevant antigen re-stimulated culture per million splenocytes was evaluated.
  • Group 1 i.e., R-DOTAP-E7 peptide and GM-CSF
  • Group 3 i.e., GM-CSF, E7 peptide, anti-CD40 Ab, and IFA
  • Group 3 was administered growth factor and a non-cationic lipid adjuvant, but did not exhibit a synergistic effect on the immune response as observed with Group 1.
  • compositions may be compared according to the present disclosure and evaluated for their effects on MDSC number in the tumor micro-environment in tumor-bearing mice.
  • R-DOTAP was used as an exemplary cationic lipid
  • E7 peptide was used as an exemplary antigen
  • the cytokine GM-CSF was used as an exemplary therapeutic factor.
  • vaccine compositions were prepared according to the disclosure and the following groups were evaluated:
  • mice Female C57BL6 mice aged 6-8 weeks old (5 mice per group) were implanted with 50,000 TC-1 cells/mouse subcutaneously in the right flank on day 0. On day 8, when all mice had tumors of ⁇ 3-4 mm in diameter, subjects from each group were with the vaccine composition of the appropriate group.
  • tumor tissue was harvested from the mice. Tumor samples were processed using GentleMACS Dissociator (Miltenyi Biotec, Auburn, CA) and the solid tumor homogenization protocol, as suggested by the manufacturer
  • the number of tumor-infiltrated MDSC (defined as CD11b + Cr-1 + cells) was analyzed within the population of CD44 + cells (marker for hematopoietic cells) using flow cytometry assay. The numbers of tumor-infiltrated cells were standardized per 1x106 of total tumor cells and presented as mean values.
  • both Group 1 i.e., R-DOTAP-E7 peptide and GM-CSF
  • Group 5 i.e., R-DOTAP-E7 and GM-CSF
  • the combination of R-DOTAP-E7 peptide and GM-CSF exhibited a synergistic effect to reduce the number of MDSC compared to the individual components.
  • the combination of R-DOTAP and GM-CSF i.e., without the administration of an antigen
  • compositions may be compared according to the present disclosure and evaluated for their effects on the number of tumor-infiltrating CD8+ T-cells in tumor-bearing mice.
  • R-DOTAP was used as an exemplary cationic lipid
  • E7 peptide was used as an exemplary antigen
  • the cytokine GM-CSF was used as an exemplary therapeutic factor.
  • vaccine compositions were prepared according to the disclosure and the following groups were evaluated:
  • mice Female C57BL6 mice aged 6-8 weeks old (5 mice per group) were implanted with 50,000 TC-1 cells/mouse subcutaneously in the right flank on day 0. On day 8, when all mice had tumors of ⁇ 3-4 mm in diameter, subjects from each group were with the vaccine composition of the appropriate group.
  • tumor tissue was harvested from the mice. Tumor samples were processed using GentleMACS Dissociator (Miltenyi Biotec, Auburn, CA) and the solid tumor homogenization protocol, as suggested by the manufacturer
  • the number of tumor-infiltrated CD8+ T-Cells were analyzed within the population of CD44 + cells (marker for hematopoietic cells) using flow cytometry assay. The numbers of tumor-infiltrated cells were standardized per 1x106 of total tumor cells and presented as mean values.
  • Group 1 i.e., R-DOTAP-E7 peptide and GM-CSF
  • Group 2 i.e., R-DOTAP-E7
  • the combination of R-DOTAP-E7 peptide and GM-CSF exhibited a synergistic effect to increase the number of tumor-infiltrated CD8+ T-Cells compared to the individual components.
  • compositions may be compared according to the present disclosure and evaluated for their effects on antigen-specific immune response in mice.
  • R-DOTAP was used as an exemplary cationic lipid
  • TRP-2 and gp100 peptides were used as an exemplary antigen
  • the cytokine GM-CSF was used as an exemplary therapeutic factor.
  • vaccine compositions were prepared according to the disclosure and the following groups were evaluated:
  • mice Female C57BL6 mice aged 6-8 weeks old (4 mice per group) were used in the study. On days 0 and 8, subjects from each group were with the vaccine composition of the appropriate group.
  • mice Seven days later (i.e., day 14 after first administration), mice were sacrificed and their spleens were harvested and processed for total lymphocytes. IFN ⁇ activity in the presence of TRP-2 and gp-100 peptides vs. irrelevant peptide control (10 ⁇ g/ml each) was assayed by ELISPOT. Values were presented as number of spots from TRP-2 and gp100 re-stimulated culture minus irrelevant antigen re-stimulated culture per million splenocytes.
  • Group 2 i.e., R-DOTAP/TRP-2/gp100 peptide/GM-CSF
  • Group 1 i.e., R-DOTAP/TRP-2/gp100 peptide/GM-CSF
  • Group 2 exhibited a statistically significant increase in antigen-specific immune response compared to Group 1, which did not include GM-CSF.

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TW201924722A (zh) * 2017-12-05 2019-07-01 美商Ｐｄｓ生技公司 用於刺激第i型干擾素基因之方法及包含陽離子脂質的組合物
CN111423504B (zh) * 2020-04-17 2021-03-26 安徽高安生物医学科技有限公司 黑色素瘤特异性抗原肽、肽复合物以及人工抗原呈递细胞
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